The infiltration and accumulation of monocytes/macrophages is a characteristic feature seen in a number of chronic inflammatory disease states such as atherosclerosis. With respect to latter, activated macrophages have been identified in every phase of the atherosclerotic lesions development-from earliest lesion termed the fatty streak to the mature and obstructive plaque. Therefore, identification of the molecular mechanisms regulating macrophage activation is of considerable scientific and therapeutic interest. [unreadable] [unreadable] The Kruppel-like Factor 2 (KLF2) is a zinc-finger transcription factor implicated in endothelial cell pro-inflammatory activation and T cell quiescence. Studies comparing the in vivo transcriptomes of monocytes purified from patients undergoing carotid endarterectomy and normal subjects by using the serial analysis of gene expression technique revealed that (1) KLF2 is expressed in human monocytes and (2) that expression is reduced in patients with coronary artery disease. Consistent with this observation, in vitro studies confirm that KLF2 expression in primary human monocytes and monocytic cell lines is reduced with activation. Adenoviral overexpression of KLF2 inhibits the lipopolysaccharide (LPS)-mediated induction of pro- inflammatory factors, cytokines, and chemokines. Conversely, siRNA mediated knockdown of KLF2 enhances pro-inflammatory gene expression. Finally, reconstitution of immunodeficient mice with KLF2 overexpressing monocytes significantly reduced carrageenan-induced acute paw inflammation and edema. Mechanistically, our studies indicate that KLF2 inhibits the key pro-inflammatory regulator NF-kB. On the basis of these observations, we hypothesize that KLF2 may serve as a negative regulator of monocyte/macrophage activation. The studies outlined in this proposal will (1) examine the effect of KLF2 overexpression and deficiency on monocyte/macrophage functions in vitro, (2) explore the molecular basis for KLF2's ability to inhibit key pro-inflammatory pathways, and (3) explore the effect of KLF2 overexpression on acute and chronic models of inflammation. The results of these investigations will provide considerable insight regarding the role of KLF2 as a regulator of macrophage activation. Furthermore, these results may provide a foundation for novel strategies to limit macrophage activation and inflammation. [unreadable] [unreadable] [unreadable]